1. Field of the Invention:
To produce its desired characteristic effects, a pharmacologically active drug must be present in appropriate concentrations at its sites of action. The concentration of a drug in vivo is not only a function of the amount of drug administered, but is also a function of the extent and rate of its adsorption, distribution, binding in tissues, biotransformation and excretion. In order to determine the proper dosage for therapeutic efficacy, it is necessary to determine the level of drug in a physiologic fluid, e.g., blood or urine.
The determination of drugs can be accomplished by various techniques, including fluorometry, gas-liquid chromatography, mass spectroscopy and competitive protein binding assays ("immunoassays"). Immunoassay techniques for drug level determination in physiologic fluids have become increasingly used for a wide variety of drugs, because such techniques are extremely sensitive, specific, and technically adaptable to processing clinical samples. Immunoassay techniques involve the use of antibodies which are specific to the drug, i.e., which bind with high affinity to the drug, but do not bind, or bind weakly, to related drugs and metabolites which may be present in the physiologic fluid.
A hapten is defined as a small molecule which by itself cannot stimulate antibody production, but can stimulate antibody production when coupled to an immunogenic carrier. The state-of-the-art of preparing antibodies to haptens such as drugs is represented by Weinryb et. al., Drug Metabolism Reviews, 10(2):271 (1979); Playfair et. al., Br. Med. Bull. 30:24 (1974); Broughton et. al., Clin. Chem., 22/6:726 (1976); and Butler, J. Immunol. Meth., 7:1 (1975 ).
One type of drug which can be assayed by such techniques is propranolol.
Propranolol is a .beta.-adrenergic inhibitor having the formula: ##STR1## Propranolol is widely used in therapy of numerous disorders, including hypertension, rhythm disturbances of the heart, angina pectoris, and hyperthyroidism. It has been found that individual variability in the level of propranolol present in the plasma, even at the same dosage levels, is common. There is also great variability in the extent to which the drug is metabolized in the liver. Consequently, it is not always possible to predict the plasma concentration or the effect of propranolol after a particular dose is administered. Because of these factors, the immunoassay technique has been found to be a clinically useful method of determining cirulatory levels of propranolol.
2. Description of the Prior Art
U.S. Pat. No. 4,026,879 is directed to an immunogen of propranolol which is propranolol coupled at the hydroxyl group through a bridging arm to an immunogenic carrier material. The immunogen claimed has the structure: ##STR2##
U.S. Pat. No. 4,070,492 is directed to a propranolol antibody prepared by injecting a host animal with the immunogen claimed in U.S. Pat. No. 4,026,879.
U.S. Pat. No. 4,241,177 is directed to an immunogen of propranolol which is the propranolol coupled at the amine nitrogen through a binding arm (R) to an immunogenic carrier material. The claimed immunogens have the structure: ##STR3##